Protective effect of milk fat globule-epidermal growth factor-factor VIII after renal ischemia-reperfusion injury in mice.
Protective effect of milk fat globule-epidermal growth factor-factor VIII after renal ischemia-reperfusion injury in mice.
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DOI：
10.1097/ccm.0b013e3182227a3d
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发表时间：
2011-09
影响因子：
8.8
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Matsuda A;Wu R;Jacob A;Komura H;Zhou M;Wang Z;Aziz MM;Wang P
肾缺血再灌注(I/R)损伤导致急性肾功能衰竭，炎症、细胞凋亡、坏死和毛细血管功能障碍是I/R损伤的特征。乳脂球-EGF因子VIII(MFG-E8)是一种膜相关分泌型糖蛋白，由免疫细胞产生，据报道参与了与组织重塑相关的多种生理过程。我们最近发现，MFG-E8治疗可通过增强对凋亡细胞的吞噬作用来减轻器官损伤、炎症反应和脓毒症后的存活率。本研究的目的是确定给予MFG-E8是否减轻肾I/R损伤。前瞻性、对照、随机的动物研究。研究所的实验室。雄性C57BL/6J小鼠(20-25g)。双侧肾蒂夹闭45min后再灌流造成肾I/R损伤。在再灌流开始时，给予重组小鼠MFG-E8(rmMFG-E8；0.4µg/20g)。在再灌流后1.5小时和20小时评估MFG-E8水平、器官损伤变量、炎症反应、组织学、细胞凋亡和毛细血管功能。在MFG-E8−/−和rmMFG-E8处理的野生型(WT)小鼠上进行了60h的存活研究。肾I/R损伤后，肾脏和脾组织中MFG-E8的mRNA和蛋白表达均显著降低。RmMFG-E8治疗可恢复肾功能，显著抑制炎症反应、细胞凋亡和坏死，并改善肾脏的毛细血管功能。在生存研究中，MFG-E8−/−小鼠表现出显著的恶化，相比之下，rmMFG-E8处理的WT小鼠与赋形剂处理的WT小鼠相比，显示出显著的生存改善。MFG-E8可作为治疗肾I/R损伤的新方法。这种保护作用似乎是通过促进细胞凋亡和改善肾脏的毛细血管功能来实现的。
Renal ischemia-reperfusion (I/R) injury causes acute renal failure and the hallmarks of renal I/R injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-EGF factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiological processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal I/R injury. Prospective, controlled, and randomized animal study. A research institute laboratory. Male C57BL/6J mice (20–25g). Renal I/R injury with bilateral renal pedicle clamping for 45 minutes, followed by reperfusion. A recombinant murine MFG-E8 (rmMFG-E8; 0.4 µg/20g) was given intraperitoneally at the beginning of reperfusion. MFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hours after reperfusion. A 60-hour survival study was conducted in MFG-E8−/− and rmMFG-E8-treated wild-type (WT) mice. After renal I/R injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with rmMFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8−/− mice showed a significant deterioration and, in contrast, rmMFG-E8-treated WT mice showed a significant improvement of survival compared with vehicle-treated WT mice. MFG-E8 can be developed as novel treatment for renal I/R injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.